European Review for Medical and Pharmacological Sciences 2020; 24: 3390-3396

Clinical efficacy of lopinavir/ritonavir

in the treatment of Coronavirus disease 2019
X.-T. YE1, Y.-L. LUO1, S.-C. XIA2, Q.-F. SUN1, J.-G. DING1, Y. ZHOU1, W. CHEN1,
X.-F. WANG1, W.-W. ZHANG1, W.-J. DU2, Z.-W. RUAN3, L. HONG1
1
Department of Infection, Rui’an People’s Hospital, Rui’an, China
2
Leading Group for COVID-19, Rui’an People’s Hospital, Rui’an, China
3
Emergency Intensive-Care Unit, Rui’an People’s Hospital, Rui’an, China

Xiaoting Ye and Yunling Luo are co-first authors

Abstract. – OBJECTIVE: The Coronavirus dis-
ease 2019 (COVID-19) which outbroke in Decem-
ber 2019 is highly contagious with a low cure
rate. In view of this, there is an urgent need
to find a more appropriate therapeutic scheme
against COVID-19. The study aimed to investi-
gate whether lopinavir/ritonavir (LPV/r) in com-
bination with other pneumonia-associated ad-
juvant drugs has a better therapeutic effect on
COVID-19.
PATIENTS AND METHODS: Totally 47 patients
with COVID-19 infection who were admitted to
Rui’an People’s Hospital between January 22 and
January 29, 2020 were collected. The patients
were divided into the test group and the control
group according to whether they had been treated
with LPV/r or not during hospitalization. Patients
in the test group were treated with LPV/r combined
with adjuvant medicine, while those in the control
group were just treated with adjuvant medicine.
The changes of body temperature, blood routine
and blood biochemistry between the two groups
were observed and compared.
RESULTS: Both groups achieved good ther-
apeutic effect with the body temperature of pa-
tients decreased gradually from admission to the
10th day of treatment. But the body temperature
of patients in the test group decreased faster than
that of the control group. Blood routine indexes
showed that compared with the control group,
the abnormal proportion of white blood cells,
lymphocytes and C-reactive protein of the test
group could be reduced to some extent. Blood
biochemical indexes exhibited that the proportion
of patients with abnormal alanine aminotransfer-
ase and aspartate aminotransferase in the test
group were lower than the control group. The
number of days for nCoV-RNA turning negative
after treatment was significantly decreased in the
test group than that in the control group.
CONCLUSIONS: Compared with the treatment
of pneumonia-associated adjuvant drugs alone,
the combination treatment with LPV/r and adju-
vant drugs has a more evident therapeutic effect
in lowering the body temperature and restoring
normal physiological mechanisms with no evi-
dent toxic and side effects. In view of these con-
clusions, we suggested that the use of LPV/r
combined with pneumonia-associated adjuvant
drugs in the clinical treatment for patients with
COVID-19 should be promoted.
Key Words:
Clinical trial, Coronavirus, Lopinavir/ritonavir, COVID-19,
China.
Introduction
Coronavirus is a general term referring to a
class of viruses and it has caused two severe respi-
ratory infectious diseases in the past two decades:
Severe Acute Respiratory Syndrome (SARS) and
Middle East Respiratory Syndrome (MERS).
SARS emerged at the end of 2002 is caused by a
novel coronavirus called SARS-CoV and a large-
scale epidemic was developed in China at that
time. By the time of August 15, 2003, a total of
8,422 confirmed cases of SARS infection had been
reported worldwide and 916 people had died of the
disease, with a fatality rate around 10%1,2. Anoth-
er highly pathogenic disease MERS is caused by
MERS-CoV virus that was initially identified in
middle-east in 20123. The MERS-CoV virus can
induce severe infection of lower respiratory tract
leading to a mortality up to 35%. Although great
efforts had been made in containing the virus from
global transmission, infected people have emerged
in over 27 countries4. In view of these, the corona-
virus pneumonia is a severe disease of both high
infection and fatality rate.
At the end of December in 2019, the first case
of novel coronavirus pneumonia was identified

Corresponding Authors: Liang Hong, MD; e-mail: Hong_liang789@163.com

3390 Zhanwei Ruan, MD; e-mail: rzwdoc1982@163.com
 Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease
in people with pneumonia who had been asso-
ciated with a seafood and live animal market
in the city of Wuhan (Hubei, China). Accord-
ing to the World Health Organization (WHO),
the novel coronavirus pneumonia has been giv-
en an official name called Coronavirus Disease
2019 (COVID-19). The 2019 Novel Coronavirus
(2019-nCoV) that causes COVID-19 is a type of
β-coronavirus, whose genetic characteristics are
significantly discriminative compared to those
of MERSr-CoV or SARSr-CoV, with nucleotide
homology up to approximately 50% and 78%, re-
spectively5. COVID-19 is highly infectious and
the viral transmission is predominantly realized
in the way of spreading by droplets or from un-
protective contacts5. In January 9, 2020, the first
case of COVID-19 death occurred. By the time of
February 16, 2020, totally 68,694 confirmed cases
of COVID-19 infection had been reported in Chi-
na and the deaths had been up to 1,667. Although
the fatality rate of COVID-19 is only 2.4% lower
than that of SARS, the number of deaths is much
bigger due to the massive infectious population.
It has been reported that the main clinical symp-
toms of patients with COVID-19 are fever, dry
cough, myalgia, fatigue, and diarrhea6. In addi-
tion, breathing difficulties and a decrease of leu-
cocytes, as well as lymphocytes, were developed
in most people, and nearly all sufferers were de-
tected with the appearance of ground-glass opac-
ity in chest CT7. Currently, no specific medicine
against COVID-19 has been developed, and the
way we can manage the patients is limited in the
symptomatic treatment and the use of the drugs
already in the market for treatment and clinical
trials. Therefore, it is urgent to find appropriate
therapeutic medicine.
Lopinavir/ritonavir (LPV/r) is a kind of prote-
ase inhibitor that has been widely applied in the
clinical treatment for HIV-1 infection8. At pres-
ent, LPV/r is one of the drugs used for second-line
treatment on anti-retrovirus. LPV/r interferes with
HIV protease to cause dysregulation of structural
and functional proteins in virus core, contributing
to the generation of immature and noninfectious
virus particles, in turn achieving the inhibition of
HIV replication9. When LPV/r is used combined
with other antiviral drugs, patients with HIV-1 in-
fection who have undergone initial treatment or
antiviral treatment can receive effective response,
such as the decrease of viral load in plasma and
the improvement of immunity. In addition, good
efficacy can also be received when LPV/r is used
alone in clinic9. It has been reported that LPV/r
has certain therapeutic effect on early SARA pa-
tients10,11. Chu et al12 made a comparison on the ef-
fect of different therapeutic regimens on patients
with SARA infection, and found that the occur-
rence rate of adverse outcomes was significantly
lower after combined use of LPV/r and ribavirin
relative compared to that after treatment with rib-
avirin alone, and physical symptoms were seen
to be much more improved. Besides, Arabi et al13
used the treatment combined with interferon β-1b,
lopinavir and ritonavir (LPV/r) for patients with
MERS infection in Saudi Arabia (with the place-
bo as control), which suggested a good response
of patients with MERS infection to LPV/r. Given
that LPV/r has produced good response in prior
clinical trials, this study focused on the role of
LPV/r in patients with COVID-19.
In the present study, totally 47 patients with
COVID-19 admitted in Rui’an People’s Hospital
were recruited. Meanwhile, the efficacy patients
received after the combination treatment with
LPV/r and routine adjuvant therapeutic drugs was
evaluated.
Patients and Methods
Patient Collection and nCoV-RNA
Positive Test
A total of 47 patients with COVID-19 infec-
tion (including 22 males and 25 females) who
were admitted to Rui’an People’s Hospital from
January 22 to 29, 2020 were recruited. Nucleic
acid samples were collected from the respiratory
tract and the nCoV-RNA was test to be positive
by quantitative PCR. The patients aged between
5 and 68, of which 9 were under 30 and 38 were
over 30. According to whether they had been
treated with LPV/r or not during hospitalization,
patients were classified into the test group (n=42)
and control group (n=5). The general clinical data
of the patients including gender, hypertension,
diabetes, CT abnormality, body temperature at
admission, oxygen saturation, hemoglobin (Hb)
concentration, C-reactive protein (CRP) are de-
tailed in Table I.
Therapeutic Schemes
Control group was treated with adjuvant
drugs only. Interferon aerosol inhalation (Scher-
ing-Plough Pharmaceutical Co., Ltd, Shanghai,
China) and arbidol tablets (Suzhou Pharmaceuti-
cal Factory of Jiangsu Wuzhong Pharmaceutical
Group Corporation, Jiangsu, China) were used for
3391
 X.-T. Ye, Y.-L. Luo, S.-C. Xia, Q.-F. Sun, J.-G. Ding, Y. Zhou et al

Table I. General clinical data of the patients.

Features Test group (n=42) Control group (n=5) p-value

Gender 0.3525
  Male 21 1
  Female 21 4
Hypertension 0.9977
  Yes 7 1
  No 35 4
Diabetes mellitus 0.9986
  Yes 7 1
  No 35 4
CT abnormality 1.0000
Yes 27 4
No 12 1
Body temperature at admission (°C) 37.36±0.67 37.92±0.61 0.7762
Oxygen saturation 97.4±1.52 95.72±9.06 0.6840
Hemoglobin (g/dL) 129.5±10.24 141.06±16.73 0.1399
C-reactive protein (CRP) 0.2670
<10 mg/L 27 2
>10 mg/L 8 2

anti-viral treatment. Usage and dosage of inter-
feron aerosol inhalation: 5 MU or equivalent dose
for adults, adding 2 ml sterile water for injection,
twice a day. Usage and dosage of arbidol tablets: 2
tablets (0.2 g) once for adults, 3 times a day, oral.
Asmeton (Compound Methoxyphenamine Cap-
sules, Daiichi Sankyo (Shanghai) Holdings Co.,
Ltd., Shanghai, China), eucalyptol limonene and
pinene enteric soft capsules (Beijing Jiuhe Phar-
maceutical Co., Ltd, Beijing, China) along with
moxifloxacin (moxifloxacin hydrochloride tab-
lets/injection, Bayer, Beijing, China) were used
against infection and inflammation (including
cough, sputum and wheezing). Usage and dosage
of asmeton: 2 tablets for patients over 15 years old
and 1 tablet for patients over 8 years old and less
than 15 years old, after meals, 3 times a day, oral.
Usage and dosage of eucalyptol limonene and
pinene enteric soft capsules: 1 tablet (0.3 g) for
acute patients (adult), 3-4 times a day and 1 tab-
let (0.3 g) for chronic patients, twice a day, taken
with cold water half an hour before meals. Usage
and dosage of moxifloxacin: 0.4 g for once a day,
oral or intravenous injection. Effective oxygen
therapies including nasal cannula, mask oxygen
inhalation and high-flow  nasal  cannula  oxygen,
if necessary, were used for dyspnea.
The test group was treated with LPV/r (Abb-
Vie Ltd, North Chicago, IL, USA) and adjuvant
drugs. The per ml of LPV/r oral liquid contained
80 mg lopinavir and 20 mg ritonavir. Usage and
dosage: 5 ml/time (400/100 mg) for adults, twice
a day or 10 ml/time (800/200 mg) once a day with
food. The schemes of adjuvant drugs were the
same as the control group.
All patients rested in bed and daily sufficient
caloric intake was ensured. The balance of wa-
ter-electrolyte in the patients was guaranteed and
the stability of internal environment was main-
tained by fluid infusion. To prevent occurrence
of new infections, antibiotics should not be used
continuously for more than 5 days, and therapy
in combination with broad-spectrum antibiotics
should be avoided. In addition, glucocorticoids
can be used in a short period of time (3-5 days) at
doses not exceeding 1-2 mg/kg/d, depending on
the patients’ situation.
Evaluation Indexes
Body temperature: the daily temperature
changes of the patients since admission were
recorded. In this study, the temperature of each
patient was recorded for 10 days (some patients
failed to record for 10 days due to their own
sake, and the unrecorded days were not includ-
ed in the subsequent data statistics). The max-
imum body temperature of each day was taken
for daily data.
Blood routine: including Hb (g/dL), total white
blood cells (WBC) (109/L), granulocyte (109/L),
platelets (PLT, 109/L), lymphocyte count (109/L)
and CRP (mg/L). The data were recorded before
and during treatment (three times), respectively.
Blood biochemistry: including alanine amino-
transferase (ALT, U/L) and aspartate aminotrans-

3392
 Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease

ative analysis of the enumeration data of the test

group and the control group. p<0.05 was consid-
ered statistically significant.

Results

Figure 1. Daily temperature variations of patients in the
two groups during 10-day hospitalization period.
ferase (AST, U/L). The data were recorded before
and after treatment (three times), respectively.
Statistical Analysis
SPSS 22.0 software (IBM Corp., Armonk,
NY, USA) was used for statistical analysis of all
the data. Fisher’s exact test was used for compar-
Comparison of Treatment
Effects in Patients
Since most patients had developed a fever, we
firstly recorded the daily temperature of patients
for a total of 10 days since the patients had re-
ceived treatment. The results exhibited that the
body temperature of the patients in the test group
decreased faster than that in the control group,
but there was no significant difference (p>0.05;
Figure 1). In addition, patients whose body tem-
perature was higher than 37.5°C at admission in
the test and control groups were compared in the
number of days of patients’ temperature recover-
ing to 37.5°C during treatment. The results indi-
cated that compared with the control group, the
patients in the test group returned to normal body
temperature in a shorter time (test group: 4.8±1.94
days vs. control group: 7.3±1.53 days, p= 0.0364).
These results suggested that patients who were
treated with LPV/r combined with pneumonia-as-

A B C

D E F

Figure 2. The percentage of patients with abnormal blood routine indexes measured three times before and after treatment from
all the patients in each group. The percentage of patients in the test and control groups with abnormal indexes including WBC
(A), lymphocyte (B), Hb (C), granulocyte (D), PLT (E) and CRP (F) was measured before and after treatment for three times. The
normal reference values: Hb, 115-150 g/L, WBC, 3.5-9.5×109/L, granulocyte, 1.8-6.3 ×109/L, PLT, 125-350 ×109/L, lymphocyte,
1.1-3.2×109/L and CRP, 0-5 mg/L. The values beyond or blow the normal reference values were considered abnormal.

3393
 X.-T. Ye, Y.-L. Luo, S.-C. Xia, Q.-F. Sun, J.-G. Ding, Y. Zhou et al

sociated adjuvant drugs were more likely to re-
turn to normal body temperature.
After comparing the difference towards fever
in patients with COVID-19 infection in the con-
trol group and the test group, we analyzed the
blood routine indexes before and after treatment
as well as the days of nCov-RNA turning nega-
tive after treatment in the two groups. The results
displayed that the abnormal proportion of WBC,
lymphocytes, CRP and PLT in the test group was
generally lower than that in the control group
after three treatments (Figure 2). Moreover, the
abnormal proportion of lymphocyte, Hb, granulo-
cyte and CRP in the test group was gradually de-
creased from the first test to the third test (Figure
2). The number of days required for nCoV-RNA
turning negative was compared and the result im-
plied that the patients in the test group are able
to turn negative in a shorter period of time (test
group: 7.8±3.09 days vs. control group: 12.0±0.82
days, p=0.0219). These results suggested that the
use of LPV/r-combined therapy could reduce the
abnormal values of biochemical indexes in pa-
tients and was more effective than use of adjuvant
therapy only.
ALT and AST Indexes of Patients
The results of the body temperature and the
blood routine demonstrated that the therapeutic
effect of LPV/r-combined therapy was better than
that of the therapy without LPV/r. After that, blood
biochemical tests were conducted for the toxic
and side effects of the drugs on liver. The main
indexes of the test were ALT and AST of patients
in the control group and the test group. By com-
paring the percentage of patients with abnormal
indexes in the first test after treatment, we found
that the abnormal percentage of ALT and AST in
the test group was lower than that in the control
group (Table II). For the test group, we concluded
that there was no significant difference in the pro-
portion of patients with indexes abnormality in
the three measurements except for a remarkable
increase in the proportion of patients with ALT
abnormality at the third measurement. These re-
sults indicated that there were no adverse effects
in liver toxic and side effects compared with the
control group after the combination treatment
with LPV/r and adjuvant drugs.
Discussion
The main purpose of this study was to eval-
uate the clinical effect of LPV/r combined with
the routine adjuvant therapeutic drugs on pa-
tients with COVID-19. As revealed, the time of
body temperature returning to normal was much
shorter in patients receiving LPV/r. In addition,
blood biochemical test suggested that the num-
ber of patients with abnormal ALT and AST in
the test group was not significantly increased
with the treatment duration, and the correspond-
ing percentage was lower than that in the con-
trol group. This indicated that there might be no
evident toxic and side effects produced on liver
after the combined use of adjuvant medicine and
LPV/r. Moreover, in patients receiving the com-
bination treatment, accelerated remission could
be seen in some clinical symptoms, such as ab-
normality of WBC, lymphocyte and C-reactive
protein. Meanwhile, the nCoV-RNA in patients
undergoing the combination treatment could be
turned negative in a shorter time. However, due
to the small sample size of the control group and
the missing of relevant data, the results above
are of some uncertainties to some extent.

Table II. The percentage of patients with abnormal ALT and AST in the test group and control group.
Time Test group Control group

The first measurement after treatment

  ALT 9.5% 25%
  AST 19% 25%
The second measurement after treatment
  ALT 11.1% NA
  AST 16.7% NA
The third measurement after treatment
  ALT 22.7% NA
  AST 18.2% NA
Note: the normal reference values: ALT: male, 9-50 U/L and female, 7-40 U/L. AST: male, 15-40 U/L and female 13-35 U/L.
The values beyond or blow the normal reference values were considered abnormal. NA means no data.

3394
 Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease
A report14 published in The Lancet in January
30, 2020 describes 99 cases with early COVID-19
who admitted in Wuhan Jinyintan Hospital from
January 1 to 20, 2020, and reveals that fever, cough
and tachypnea are the most common symptoms
occurring in sufferers. Consistently, over 80% pa-
tients in this study also developed fever. Further-
more, similar to a previous study on the epidemic
of COVID-195, most patients in our research har-
bored imaging characteristic of viral pneumonia
and a relative lower count of WBC in the early
stage. Our statistical result further verified the typ-
ical symptoms of patients with COVID-19.
It is established that SARS-CoV, MERS-CoV,
and 2019-nCoV are coronavirus and they are all
RNA viruses like HIV that can be translated into
functional viral proteins in the way of protease
hydrolysis during viral replication and assembly
process, which makes it possible to impede viral
replication process via inhibiting protease hydro-
lysis. An article published in the Nature Reviews
Drug Discovery15 in February 2020 describes that
the non-structural proteins encoded by 2019-nCoV
genome are key players involved in the viral life
cycle, such as 3-chymotrypsin-like protease, pa-
pain-like protease, helicase and RNA-dependent
RNA polymerase, and these four proteases have
been observed to have highly conservative cata-
lytic sites. In addition, structural analysis in this
article reveals that the key drug-binding pockets
across SARS-CoV, MERS-CoV and 2019-nCoV
proteases might be conservative and can be used
as potential antiviral targets. Thus, it prompts us
to pay more attention on the potential of the anti-
viral agents that have been approved or are in de-
velopment for treating infections caused by HIV,
hepatitis B virus (HBV), hepatitis C virus (HCV)
and influenza. Among the drugs, LPV/r, daruna-
vir and ASC09/Ritonavir are all HIV protease
inhibitors and have been studied in this research.
At present, there is no available specific med-
icine against COVID-19. LPV/r is generally used
in the treatment for HIV infection and it is able to
cause the suppression of HIV-1 replication16. Chu
et al12 indicated that use of LPV/r can significant-
ly lead to the reduction of acute respiratory dis-
tress syndrome development and mortality that
caused by SARS infection. In addition, for the
therapeutic response of patients with COVID-19
to LPV/r, some scholars have paid much atten-
tion on and made some discussions recently, yet
the specific results have not been reported17. In
the present study, LPV/r was used for COVID-19
treatment and good responses were achieved in
the remission of fever and inflammation. How-
ever, there are some limitations that mainly re-
fer to the small sample size of the control group.
Besides, the missing data during treatment make
the results not precise enough, and no statisti-
cal analysis has been performed towards the side
effects of LPV/r on gastrointestinal track like
diarrhea. Therefore, for future analysis, sample
size should be enlarged to make the results more
accurate and a systemic study should be carried
out on whether LPV/r can cause side effects on
gastrointestinal track in patients with COVID-19
infection.
Conclusions
We proved that the combination treatment
of LPV/r and routine adjuvant medicine against
pneumonia could produce much better efficacy
on patients with COVID-19 infection compared to
treatment with adjuvant medicine alone. Hence, we
suggest to widely apply the combination treatment
in treating patients with COVID-19 infection.
Ethics Committee Approval
Ethical approval was given by the Medical Ethics Commit-
tee of Rui’an People’s Hospital, with the following reference
number: YJ2020013.
Funding Acknowledgements
Zhejiang Natural Science Foundation: experimental study
on the role of IL-6-INDUCED exosome pathway in promot-
ing invasion and metastasis of hepatocellular carcinoma by
omitting microRNA-133a-3p LY19H160015.
Medical Science and Technology Project of Zhejiang Prov-
ince: Study on the synergistic lethal effect and molecular
mechanism of ALK targeting in TP53 mutant intrahepatic
Cholangiocarcinoma 2019324310.
Ruian Science and Technology Bureau (MS2020023).
Conflict of Interests
The authors declare that they have no conflict of interests.
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